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hERG (the human '' Ether-à-go-go''-Related Gene) is a gene () that codes for a protein known as Kv11.1, the alpha
subunit Subunit may refer to: *Subunit HIV vaccine, a class of HIV vaccine *Protein subunit, a protein molecule that assembles with other protein molecules *Monomer, a molecule that may bind chemically to other molecules to form a polymer *Sub-subunit, a ...
of a
potassium ion channel Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of ce ...
. This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution to the electrical activity of the heart: the hERG channel mediates the repolarizing ''I''Kr current in the
cardiac action potential The cardiac action potential is a brief change in voltage ( membrane potential) across the cell membrane of heart cells. This is caused by the movement of charged atoms (called ions) between the inside and outside of the cell, through proteins c ...
, which helps coordinate the heart's beating. When this channel's ability to conduct electrical current across the cell membrane is inhibited or compromised, either by application of drugs or by rare mutations in some families, it can result in a potentially fatal disorder called
long QT syndrome Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, d ...
. Conversely, genetic mutations that increase the current through these channels can lead to the related inherited heart rhythm disorder
Short QT syndrome Short QT syndrome (SQT) is a very rare genetic disease of the electrical system of the heart, and is associated with an increased risk of abnormal heart rhythms and sudden cardiac death. The syndrome gets its name from a characteristic feature s ...
. A number of clinically successful drugs in the market have had the tendency to inhibit hERG, lengthening the QT and potentially leading to a fatal irregularity of the heartbeat (a ventricular tachyarrhythmia called
torsades de pointes ''Torsades de pointes, torsade de pointes'' or ''torsades des pointes'' (TdP) (, , translated as "twisting of peaks") is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia t ...
). This has made hERG inhibition an important
antitarget In pharmacology, an antitarget (or off-target) is a receptor, enzyme, or other biological target that, when affected by a drug, causes undesirable side-effects. During drug design and development, it is important for pharmaceutical companies to ens ...
that must be avoided during drug development. hERG has also been associated with modulating the functions of some cells of the nervous system and with establishing and maintaining cancer-like features in leukemic cells.


Function

hERG forms the major portion of one of the ion channel proteins (the 'rapid' delayed rectifier current (''I''Kr)) that conducts potassium (K+) ions out of the muscle cells of the heart (
cardiac myocytes Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate Muscle tissue, muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striat ...
), and this current is critical in correctly timing the return to the resting state (
repolarization In neuroscience, repolarization refers to the change in membrane potential that returns it to a negative value just after the depolarization phase of an action potential which has changed the membrane potential to a positive value. The repolarizat ...
) of the cell membrane during the cardiac action potential. Sometimes, when referring to the pharmacological effects of drugs, the terms "hERG channels" and ''I''Kr are used interchangeably, but, in the technical sense, "hERG channels" can be made only by scientists in the laboratory; in formal terms, the naturally occurring channels in the body that include hERG are referred to by the name of the electrical current that has been measured in that cell type, so, for example, in the heart, the correct name is ''I''Kr. This difference in nomenclature becomes clearer in the controversy as to whether the channels conducting ''I''Kr include other subunits (e.g., beta subunits) or whether the channels include a mixture of different types (
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
s) of hERG, but, when the originally-discovered form of hERG is experimentally transferred into cells that previously lacked hERG (i.e.,
heterologous The term heterologous has several meanings in biology. Gene expression In cell biology and protein biochemistry, heterologous expression means that a protein is experimentally put into a cell that does not normally make (i.e., express) that ...
expression), a potassium ion channel is formed, and this channel has many signature features of the cardiac 'rapid' delayed rectifier current (''I''Kr), including ''I''Kr's inward rectification that results in the channel producing a 'paradoxical resurgent current' in response to repolarization of the membrane.


Structure

A detailed atomic structure for hERG based on
X-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
is not yet available, but structures have recently been solved by electron microscopy. In the laboratory the heterologously expressed hERG potassium channel comprises 4 identical alpha subunits, which form the channel's pore through the
plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
. Each hERG subunit consists of 6 transmembrane
alpha helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...
, numbered S1-S6, a pore helix situated between S5 and S6, and cytoplasmically located N- and
C-termini The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
. The S4 helix contains a positively charged
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
or
lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
amino acid residue at every 3rd position and is thought to act as a voltage-sensitive sensor, which allows the channel to respond to voltage changes by changing conformations between conducting and non-conducting states (called 'gating'). Between the S5 and S6 helices, there is an extracellular loop (known as 'the turret') and 'the pore loop', which begins and ends extracellularly but loops into the plasma membrane; the pore loop for each of the hERG subunits in one channel faces into the ion-conducting pore and is adjacent to the corresponding loops of the 3 other subunits, and together they form the selectivity filter region of the channel pore. The selectivity sequence, SVGFG, is very similar to that contained in bacterial KcsA channels. Although a full crystal structure for hERG is not yet available, a structure has been found for the cytoplasmic N-terminus, which was shown to contain a
PAS domain A Per-Arnt-Sim (PAS) domain is a protein domain found in all kingdoms of life. Generally, the PAS domain acts as a molecular sensor, whereby small molecules and other proteins associate via binding of the PAS domain. Due to this sensing capability ...
(aminoacid 26–135) that slows the rate of deactivation.


Genetics

Loss-of-function mutations in this channel may lead to
long QT syndrome Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, d ...
(LQT2), while gain-of-function mutations may lead to
short QT syndrome Short QT syndrome (SQT) is a very rare genetic disease of the electrical system of the heart, and is associated with an increased risk of abnormal heart rhythms and sudden cardiac death. The syndrome gets its name from a characteristic feature s ...
. Both clinical disorders stem from ion channel dysfunction (so-called
channelopathies Channelopathies are a group of diseases caused by the dysfunction of ion channel subunits or their interacting proteins. These diseases can be inherited or acquired by other disorders, drugs, or toxins. Mutations in genes encoding ion channels, wh ...
) that can lead to the risk of potentially fatal cardiac
arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
s (e.g., ''
torsades de pointes ''Torsades de pointes, torsade de pointes'' or ''torsades des pointes'' (TdP) (, , translated as "twisting of peaks") is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia t ...
''), due to repolarization disturbances of the cardiac action potential. There are far more hERG mutations described for long QT syndrome than for short QT syndrome.


Drug interactions

This channel is also sensitive to drug binding, as well as decreased extracellular potassium levels, both of which can result in decreased channel function and drug-induced (acquired) long QT syndrome. Among the drugs that can cause QT prolongation, the more common ones include antiarrhythmics (especially Class 1A and Class III), anti-psychotic agents, and certain antibiotics (including quinolones and macrolides). Although there exist other potential targets for cardiac adverse effects, the vast majority of drugs associated with acquired QT prolongation are known to interact with the hERG potassium channel. One of the main reasons for this phenomenon is the larger inner vestibule of the hERG channel, thus providing more space for many different drug classes to bind and block this potassium channel. hERG containing channels are blocked by
amiodarone Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia (VT), ventricular fibrillation (VF), and wide complex tachycardia, as well as atrial fibrilla ...
.
Thioridazine Thioridazine (Mellaril or Melleril) is a first generation antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis. The branded product was withdrawn worldwide ...
causes peculiarly severe QTc prolongation by blocking hERG and was withdrawn by the manufacturer for this reason.


Drug development considerations

Due to the documented potential of QT-interval-prolonging drugs, the United States Food and Drug Administration issued recommendations for the establishment of a cardiac safety profile during pre-clinical drug development: ICH S7B. The nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals, issued as CHMP/ICH/423/02, adopted by CHMP in May 2005. Preclinical hERG studies should be accomplished in GLP environment.


Naming

The hERG gene was first named and described in a paper by Jeff Warmke and Barry Ganetzky, then both at the
University of Wisconsin–Madison A university () is an educational institution, institution of higher education, higher (or Tertiary education, tertiary) education and research which awards academic degrees in several Discipline (academia), academic disciplines. Universities ty ...
. The hERG gene is the human homolog of the ''Ether-à-go-go'' gene found in the
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
fly; ''Ether-à-go-go'' was named in the 1960s by William D. Kaplan and William E. Trout, III, while at the City of Hope Hospital in
Duarte, California Duarte () is a city in Los Angeles County, California, United States. As of the 2020 census, the city population was 21,727. It is bounded to the north by the San Gabriel Mountains, to the north and west by the cities of Bradbury and Monrovia ...
. When flies with mutations in the ''Ether-à-go-go'' gene are anaesthetised with
ether In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...
, their legs start to shake, like the dancing at the then popular
Whisky a Go Go The Whisky a Go Go (informally nicknamed "the Whisky") is a historic nightclub in West Hollywood, California, United States. It is located at 8901 Sunset Boulevard on the Sunset Strip, corner North Clark Street, opposite North San Vicente Boul ...
nightclub in
West Hollywood, California West Hollywood is a city in Los Angeles County, California, United States. Incorporated in 1984, it is home to the Sunset Strip. As of the 2020 United States Census, 2020 U.S. Census, its population was 35,757. It is considered one of the most ...
.


Interactions

HERG has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with the 14-3-3 epsilon protein, encoded by
YWHAE 14-3-3 protein epsilon is a protein that in humans is encoded by the ''YWHAE'' gene. Function This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This hi ...
.


See also

*
Voltage-gated potassium channel Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized ce ...


References


Further reading

* * * * *


External links


GeneReviews/NIH/NCBI/UW entry on Romano-Ward Syndrome




* ttps://web.archive.org/web/20101129122954/http://schizophreniaforum.org/new/detail.asp?id=1521 Special K: Primate-specific Potassium Channel Variant Implicated in Schizophrenia-
Schizophrenia Research Forum Schizophrenia Research Forum is a web knowledge environment dedicated to news, information resources, and discussion about research on schizophrenia. It hosts a number of resources such as What We Know About Schizophrenia, Animal Models and Drugs in ...
. {{Ion channels, g3 Ion channels PAS-domain-containing proteins